1. A 58-year-old man with chronic-phase CML has been on imatinib for three years with a sustained major molecular response. Over two consecutive measurements his BCR-ABL1 transcript level rises and he loses his major molecular response. BCR-ABL1 kinase-domain mutation analysis is performed and detects the T315I mutation. His history includes peripheral arterial disease and a prior myocardial infarction. Which therapeutic choice is most appropriate?
A) Switch to dasatinib, accepting its pleural effusion risk
B) Switch to asciminib, which is active against T315I through its allosteric myristoyl-pocket mechanism and avoids the dose-dependent arterial occlusive risk that makes ponatinib hazardous in this vasculopath
C) Increase the imatinib dose to overcome the T315I mutation
D) Switch to nilotinib, whose greater potency overcomes T315I
E) Continue imatinib and add an allogeneic stem cell transplant referral as the only option
ANSWER: B
Rationale:
Option B is correct. Loss of major molecular response with a confirmed T315I gatekeeper mutation restricts the effective options to the two agents active against T315I: ponatinib (ATP-competitive, designed to bypass the gatekeeper) and asciminib (an allosteric STAMP inhibitor active against T315I at the higher 200 mg twice-daily dose). In a patient with established peripheral arterial disease and prior myocardial infarction, ponatinib's dose-dependent arterial occlusive events make it especially hazardous, so asciminib — with a different toxicity profile — is the better-matched choice.
Option A: Option A is incorrect. Dasatinib does not have reliable activity against T315I, so it would not control the resistant clone regardless of its toxicity profile.
Option C: Option C is incorrect. Dose escalation does not overcome T315I; the altered gatekeeper blocks imatinib binding at any achievable concentration.
Option D: Option D is incorrect. Nilotinib does not overcome T315I and itself carries arterial occlusive and QTc risks, making it doubly inappropriate here.
Option E: Option E is incorrect. Effective pharmacologic options (asciminib, and ponatinib if needed) exist, so continuing ineffective imatinib is wrong; transplant may be considered in eligible patients with advanced-phase disease but is not the sole option in chronic phase with an available active agent.
2. A 64-year-old woman with CML on nilotinib has her dose increased after a suboptimal molecular response. One week later she reports new exertional chest discomfort. An electrocardiogram shows a corrected QT interval (QTc) of 495 ms (baseline had been 430 ms). She admits she recently began taking each dose with breakfast. Which is the most appropriate immediate management?
A) Continue nilotinib at the increased dose and repeat the ECG in three months
B) Reassure her that nilotinib does not affect the QT interval and attribute the findings to anxiety
C) Double the nilotinib dose to accelerate the molecular response, since chest discomfort is unrelated
D) Hold nilotinib (the QTc of 495 ms exceeds the threshold at which the drug should be withheld), correct the administration error by restoring strict fasting, evaluate the chest discomfort for ischemia given nilotinib's vascular risk, and review for other QTc-prolonging drugs and electrolyte abnormalities before cautious resumption
E) Switch immediately to imatinib without addressing the QTc or the chest pain
ANSWER: D
Rationale:
Option D is correct. Nilotinib prolongs the QTc in a concentration-dependent fashion, and taking it with food markedly increases exposure — both contributing to a QTc that has risen to 495 ms, above the threshold (roughly 480 ms) at which the drug should be held. The integrated response is to hold nilotinib, correct the food-administration error (restore strict fasting), evaluate the new exertional chest discomfort for ischemia given nilotinib's known arterial/cardiovascular risk, and check for other QTc-prolonging agents and electrolyte derangements before any cautious resumption.
Option A: Option A is incorrect. A QTc of 495 ms with new symptoms requires holding the drug now, not continuing at the higher dose with delayed monitoring.
Option B: Option B is incorrect. Nilotinib clearly prolongs the QTc; dismissing the abnormal ECG and symptoms as anxiety is unsafe.
Option C: Option C is incorrect. Doubling the dose would raise the concentration further and worsen the concentration-dependent QTc prolongation, the opposite of what is needed.
Option E: Option E is incorrect. Switching agents without first holding the drug, correcting the food error, and evaluating the chest pain ignores the immediate arrhythmic and ischemic risks.
3. A 70-year-old man with CML has been taking dasatinib 100 mg twice daily for several months. He develops progressive exertional dyspnea and a dry cough. A chest radiograph shows a moderate right-sided pleural effusion. He is afebrile, with normal white count and no infiltrate; thoracentesis yields an exudate with no organisms and no malignant cells. Which is the most appropriate interpretation and management?
A) This represents disease progression to a malignant pleural effusion and warrants switching to chemotherapy
B) This is most likely a community-acquired pneumonia and should be treated with antibiotics while dasatinib is continued unchanged
C) This is dasatinib-associated pleural effusion, a characteristic toxicity of the drug; management is to interrupt dasatinib until the effusion improves, then resume at a reduced dose or convert to once-daily dosing (which lowers effusion risk), with diuretics and a short corticosteroid course as needed
D) This is pulmonary arterial hypertension and mandates immediate permanent discontinuation of all BCR-ABL therapy
E) This is drug-induced interstitial lung disease and requires high-dose corticosteroids with permanent dasatinib discontinuation
ANSWER: C
Rationale:
Option C is correct. Pleural effusion is the characteristic toxicity of dasatinib, occurring in a substantial fraction of patients particularly on twice-daily dosing. A non-infectious exudative effusion without malignant cells in a patient on twice-daily dasatinib fits this diagnosis. Management is to interrupt the drug until the effusion improves and then resume at a reduced dose or convert to once-daily dosing, which lowers effusion risk while preserving efficacy; supportive diuresis and a short corticosteroid course may help.
Option A: Option A is incorrect. The pleural fluid shows no malignant cells, arguing against a malignant progression-related effusion, so abandoning targeted therapy for chemotherapy is unwarranted.
Option B: Option B is incorrect. He is afebrile with a normal white count, no infiltrate, and no organisms, making pneumonia unlikely; continuing full-dose dasatinib ignores the likely drug cause.
Option D: Option D is incorrect. Pulmonary arterial hypertension is a rarer dasatinib complication with a different presentation (it would not produce this exudative effusion picture), and effusion is managed with interruption and dose modification rather than mandatory permanent discontinuation of all therapy.
Option E: Option E is incorrect. The picture is a pleural effusion, not the diffuse parenchymal ground-glass pattern of interstitial lung disease, so ILD-directed management is not indicated.
4. A 54-year-old never-smoker is diagnosed with metastatic lung adenocarcinoma. Molecular testing shows an EGFR exon 19 deletion. Staging brain MRI reveals several small, asymptomatic brain metastases. She has no neurologic deficits. Which first-line approach is most appropriate?
A) Begin osimertinib as first-line therapy, because its high CNS penetration controls the asymptomatic brain metastases as well as systemic disease, allowing upfront whole-brain radiation to be deferred and its neurocognitive sequelae avoided
B) Begin a first-generation EGFR TKI such as gefitinib, reserving osimertinib until T790M emerges
C) Treat with whole-brain radiation first and withhold systemic therapy until the brain disease is controlled
D) Begin platinum-based chemotherapy, since brain metastases preclude the use of targeted therapy
E) Begin crizotinib, since it has the best CNS penetration of the available agents
ANSWER: A
Rationale:
Option A is correct. For an EGFR-mutant (exon 19 deletion) patient with asymptomatic brain metastases, osimertinib is the preferred first-line agent precisely because of its exceptional CNS penetration: it achieves high CNS response rates and can serve as initial management of the brain disease, allowing upfront whole-brain radiation — and its neurocognitive harms — to be deferred. It is also the first-line standard for systemic disease regardless of baseline T790M status.
Option B: Option B is incorrect. Osimertinib is preferred first-line over first-generation agents, and its CNS penetration is far superior; waiting for T790M before using it forgoes that benefit.
Option C: Option C is incorrect. CNS-penetrant osimertinib can control asymptomatic brain metastases, so upfront whole-brain radiation with delayed systemic therapy is not the preferred initial strategy.
Option D: Option D is incorrect. Brain metastases do not preclude targeted therapy; an EGFR-mutant tumor should receive an EGFR TKI rather than upfront chemotherapy.
Option E: Option E is incorrect. Crizotinib is an ALK/ROS1 inhibitor with poor CNS penetration and no role in EGFR-mutant disease.
5. A 61-year-old woman with EGFR-mutant (L858R) NSCLC has had an excellent response to erlotinib for 14 months. Surveillance imaging now shows new and enlarging pulmonary lesions consistent with progression. Plasma circulating tumor DNA testing detects the original L858R mutation plus a newly acquired T790M mutation. Which is the most appropriate next step?
A) Increase the erlotinib dose, since T790M reflects inadequate drug exposure
B) Add afatinib to erlotinib, as the combination overcomes T790M
C) Switch to osimertinib, the third-generation EGFR TKI specifically active against the T790M-mutant receptor while relatively sparing wild-type EGFR
D) Switch to crizotinib, since acquired resistance indicates the tumor is now ALK-driven
E) Discontinue targeted therapy and begin best supportive care, as T790M-mutant disease is untreatable
ANSWER: C
Rationale:
Option C is correct. T790M is the most common acquired resistance mechanism to first-generation EGFR TKIs, and its detection on plasma circulating tumor DNA at progression directs therapy to osimertinib, which was engineered to inhibit the EGFR receptor carrying both the sensitizing mutation and T790M while relatively sparing wild-type EGFR. This vignette is the textbook indication for switching to osimertinib.
Option A: Option A is incorrect. T790M is a binding-altering resistance mutation, not a consequence of low exposure, so a dose increase will not restore control.
Option B: Option B is incorrect. Afatinib (a second-generation agent) does not overcome T790M, and combining it with erlotinib does not address the mutation.
Option D: Option D is incorrect. The tumor remains EGFR-driven (now with added T790M); it has not become ALK-driven, so crizotinib is inappropriate.
Option E: Option E is incorrect. T790M-mutant disease is specifically treatable with osimertinib, so moving to supportive care alone is wrong.
6. A 49-year-old man with EGFR-mutant (exon 19 deletion) NSCLC has been on first-line osimertinib for 16 months. He now has rapid clinical decline with new bulky liver metastases and a sharply rising LDH. A plasma circulating tumor DNA panel is uninformative (no actionable resistance alteration detected). Which is the most appropriate next diagnostic step?
A) Restart his original first-generation EGFR TKI, since osimertinib resistance reliably reverts to a T790M-driven, gefitinib-sensitive state
B) Conclude that no resistance mechanism is present and continue osimertinib unchanged
C) Begin empiric MET-inhibitor therapy, presuming MET amplification without further testing
D) Switch to ponatinib, which covers the full range of osimertinib resistance mutations
E) Perform a tissue rebiopsy, because resistance to first-line osimertinib is heterogeneous (including C797S, MET or HER2 amplification, and histologic transformation to small cell lung cancer in roughly 15% of cases), an uninformative plasma result does not exclude these mechanisms, and the rapid clinical decline with rising LDH raises concern for small cell transformation, which only tissue can diagnose
ANSWER: E
Rationale:
Option E is correct. Resistance to first-line osimertinib has no single dominant mechanism — it spans tertiary EGFR mutations (C797S), bypass-pathway amplifications (MET, HER2), and histologic transformation to small cell lung cancer in about 15% of cases. A negative or uninformative plasma circulating tumor DNA result does not exclude these mechanisms, and the aggressive picture here (bulky visceral disease, rising LDH) specifically raises concern for small cell transformation, which can be diagnosed only on tissue. Tissue rebiopsy is therefore the correct next step.
Option A: Option A is incorrect. Post-osimertinib resistance is heterogeneous and does not predictably revert to T790M-driven, first-generation-sensitive disease.
Option B: Option B is incorrect. Clear clinical and radiographic progression indicates a resistance mechanism is operating; an uninformative plasma test does not mean none exists.
Option C: Option C is incorrect. Empiric MET-inhibitor therapy without confirming the mechanism is inappropriate when several distinct mechanisms — including transformation — are possible and tissue can distinguish them.
Option D: Option D is incorrect. Ponatinib is a BCR-ABL1 agent with no activity against EGFR resistance mechanisms and no role here.
7. A 41-year-old never-smoker with ALK-positive NSCLC has been on crizotinib for 11 months with excellent control of her thoracic and abdominal disease. Routine surveillance brain MRI now reveals two new small brain metastases; her systemic disease remains stable and she is neurologically asymptomatic. Which is the most appropriate next step?
A) Discontinue ALK-directed therapy and begin palliative chemotherapy, as the appearance of brain metastases signals systemic treatment failure
B) Switch to a CNS-penetrant ALK inhibitor such as alectinib or lorlatinib, because crizotinib penetrates the CNS poorly and ALK-positive disease is prone to brain metastasis, so isolated CNS progression with controlled systemic disease reflects the expected crizotinib failure mode rather than failure of ALK-directed therapy as a strategy
C) Continue crizotinib unchanged and simply repeat the MRI in three months
D) Double the crizotinib dose to force more drug across the blood-brain barrier
E) Question the ALK diagnosis and treat the brain lesions as a separate primary tumor
ANSWER: B
Rationale:
Option B is correct. Crizotinib penetrates the CNS poorly, while ALK-positive NSCLC carries a high propensity for brain metastasis; the combination produces isolated CNS progression while systemic disease stays controlled — the characteristic crizotinib failure mode. The appropriate response is to switch to a CNS-penetrant ALK inhibitor (alectinib or lorlatinib) that can control the brain disease, rather than abandoning ALK inhibition.
Option A: Option A is incorrect. Systemic disease is controlled, so this is not systemic treatment failure, and chemotherapy discards an effective targeted strategy.
Option C: Option C is incorrect. New brain metastases on a poorly CNS-penetrant drug warrant a change to a CNS-penetrant agent, not watchful waiting.
Option D: Option D is incorrect. Doubling crizotinib does not reliably overcome its intrinsic poor CNS penetration; switching agents is the rational solution.
Option E: Option E is incorrect. CNS progression here is the expected behavior of the known ALK-positive tumor under a poorly penetrant drug, not evidence of a separate primary cancer.
8. A 55-year-old man with newly diagnosed ALK-positive NSCLC begins brigatinib. On day 5 of therapy he develops acute dyspnea and cough, and his oxygen saturation has fallen. A chest CT shows new bilateral opacities. He is afebrile with no leukocytosis. Which is the most appropriate interpretation and action?
A) This is rapid disease progression and warrants immediate escalation of the brigatinib dose
B) This is most likely bacterial pneumonia and should be treated with antibiotics while brigatinib is continued
C) This is hypercholesterolemia-related and should be managed by starting a statin
D) This is brigatinib's characteristic early-onset pulmonary toxicity, which typically occurs within the first 7 days of therapy; brigatinib should be interrupted promptly and the patient supported and evaluated, with rechallenge or discontinuation decisions made based on severity and recurrence
E) This is QTc prolongation and should be managed with electrolyte repletion alone while continuing brigatinib
ANSWER: D
Rationale:
Option D is correct. Brigatinib has a distinctive early-onset pulmonary toxicity — dyspnea and hypoxia, often with bilateral opacities — that characteristically appears within the first 7 days of therapy. The day-5 onset in an afebrile patient without leukocytosis fits this entity, and the correct action is to interrupt brigatinib promptly while supporting and evaluating the patient; decisions about rechallenge versus discontinuation depend on severity and any recurrence.
Option A: Option A is incorrect. New pulmonary findings on day 5 fit early brigatinib pulmonary toxicity, not rapid progression, and increasing the dose would worsen the toxicity.
Option B: Option B is incorrect. The afebrile, non-leukocytic presentation with the characteristic early timing points to drug toxicity rather than bacterial pneumonia, and continuing the drug is unsafe.
Option C: Option C is incorrect. Hypercholesterolemia is a lorlatinib feature and would not produce acute dyspnea, hypoxia, and bilateral opacities.
Option E: Option E is incorrect. The presentation is pulmonary, not an asymptomatic ECG change; managing it as QTc prolongation while continuing the drug misses the diagnosis.
9. A 46-year-old woman with ROS1-rearranged NSCLC has had a good response to crizotinib for 19 months. She now develops radiographic progression. Repeat molecular testing identifies a newly acquired ROS1 G2032R solvent-front mutation. Which agent is most appropriate for her acquired resistance?
A) Osimertinib, since it targets the kinase domain shared by ROS1 and EGFR
B) Nilotinib, which overcomes solvent-front mutations across kinase families
C) Repotrectinib, a next-generation ROS1 inhibitor with demonstrated activity against the ROS1 G2032R solvent-front mutation, which is the dominant resistance mechanism after a prior ROS1 TKI
D) A higher dose of crizotinib, since G2032R reflects insufficient drug exposure
E) Imatinib, because its broad kinase activity includes ROS1 fusions
ANSWER: C
Rationale:
Option C is correct. The ROS1 G2032R solvent-front mutation is the dominant acquired resistance mechanism after a prior ROS1 TKI such as crizotinib, and it confers resistance to earlier ROS1 agents. Repotrectinib is a next-generation ROS1 inhibitor specifically active against G2032R, making it the appropriate choice for this acquired resistance.
Option A: Option A is incorrect. Osimertinib is an EGFR-directed agent; ROS1 and EGFR are distinct kinases with distinct inhibitors, and osimertinib has no role against ROS1 G2032R.
Option B: Option B is incorrect. Nilotinib is a BCR-ABL1 agent and does not address ROS1 solvent-front resistance.
Option D: Option D is incorrect. G2032R is a binding-altering resistance mutation, not a problem of inadequate exposure, so dose escalation of crizotinib will not restore control.
Option E: Option E is incorrect. Imatinib targets BCR-ABL1/KIT/PDGFRA, not ROS1 fusions, and is not used for ROS1-positive NSCLC.
10. A 50-year-old woman with chronic-phase CML has been on imatinib for six years and has maintained a deep molecular response (BCR-ABL1 at or below 0.01% on the international scale) for the past three and a half years. She asks whether she can stop therapy. She meets accepted criteria for a treatment-free remission attempt. Which statement best describes the appropriate plan and what to anticipate?
A) A monitored treatment-free remission attempt is reasonable: discontinue the TKI with frequent molecular monitoring, recognizing that molecular relapse, if it occurs, usually happens within the first 6 months and is treated by promptly resuming the prior TKI (with nearly all patients regaining response), and that a self-limited withdrawal syndrome of musculoskeletal pain occurs in roughly 30% of patients after stopping
B) She must continue imatinib indefinitely, because stopping a TKI in CML always results in rapid blast-phase transformation
C) She may stop the TKI permanently with no further monitoring, since a sustained deep molecular response means the leukemia is cured
D) She should switch to a more potent second-generation TKI before any discontinuation attempt, regardless of her current response
E) She should stop the TKI and begin allogeneic stem cell transplantation to consolidate the remission
ANSWER: A
Rationale:
Option A is correct. A patient in sustained deep molecular response (here at or below 0.01% for more than 2–3 years) who meets criteria may attempt treatment-free remission. The plan is to discontinue under frequent molecular monitoring: molecular relapse, when it happens, typically occurs within the first 6 months and is managed by promptly resuming the prior TKI, with nearly all patients regaining response. A self-limited withdrawal syndrome of musculoskeletal pain occurs in roughly 30% of patients after discontinuation and should be anticipated.
Option B: Option B is incorrect. Discontinuation in eligible patients does not uniformly cause blast-phase transformation; monitored treatment-free remission is an accepted goal.
Option C: Option C is incorrect. Treatment-free remission requires ongoing close molecular monitoring (because relapse can occur), and a deep molecular response is not equivalent to cure.
Option D: Option D is incorrect. Switching to a more potent agent is not required before a discontinuation attempt in a patient already in sustained deep molecular response on imatinib.
Option E: Option E is incorrect. Allogeneic transplant is not indicated to consolidate a chronic-phase deep molecular response; it carries substantial risk and is reserved for other settings.
11. A 60-year-old man with EGFR-mutant NSCLC is responding well to osimertinib. He is found to have latent tuberculosis, and the clinic proposes a rifampin-containing regimen. Rifampin is a strong CYP3A4 inducer, and osimertinib is a CYP3A4 substrate. Which management is most appropriate?
A) Proceed with rifampin and make no change to osimertinib, since the interaction is negligible
B) Reduce the osimertinib dose during rifampin therapy to avoid toxicity
C) Stop osimertinib entirely for the duration of latent TB treatment
D) Switch osimertinib to a first-generation EGFR TKI, which is unaffected by rifampin
E) Avoid rifampin and use a non-inducing latent-TB regimen in consultation with infectious disease; if a strong CYP3A4 inducer is truly unavoidable, increase the osimertinib dose (for example to 160 mg/day) with monitoring, because rifampin can reduce osimertinib exposure by roughly 78% and risk loss of disease control
ANSWER: E
Rationale:
Option E is correct. Rifampin strongly induces CYP3A4 and can lower osimertinib exposure by roughly 78%, enough to jeopardize disease control. The preferred approach is to avoid rifampin and select a non-inducing latent-TB regimen in coordination with infectious disease. If a strong CYP3A4 inducer is genuinely unavoidable, the osimertinib dose can be increased (for example to 160 mg/day) with monitoring to partially compensate for the induced clearance.
Option A: Option A is incorrect. The interaction is substantial (a ~78% reduction in exposure), so making no change risks loss of cancer control.
Option B: Option B is incorrect. Induction lowers osimertinib levels, so a dose reduction would worsen the underexposure — the wrong direction.
Option C: Option C is incorrect. Stopping osimertinib for the months of latent-TB therapy needlessly risks cancer progression when a non-inducing regimen or dose adjustment is available.
Option D: Option D is incorrect. First-generation EGFR TKIs are also CYP3A4 substrates and are likewise affected by rifampin, and switching away from osimertinib sacrifices its superior efficacy and CNS coverage.
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